Production of unsaturated carbocyclic ketones

ABSTRACT

PREPARATION OF A,B-UNSATURATED CARBOCYCLIC KETONES BY REACTING A METHYLENE PHOSPHONIUM YLID OR A MONO-SUBSTITUTED METHYLENE PHOSPHONIUM YLID WITH AN ENOL LACTONE.

United States Patent 3,658,847 PRODUCTION OF UNSATURATED CARBOCYCLICKETONES John H. Fried, Palo Alto, Calif., assignor to SyntexCorporation, Panama, Panama No Drawing. Continuation-impart ofapplications Ser. No. 686,477, Dec. 4, 1967, now Patent No. 3,524,886,and Ser. No. 747,466, July 25, 1968. This application Nov. 4, 1968, Ser.No. 773,356

Int. Cl. C0711 15/04 U.S. Cl. 260-340.9 Claims ABSTRACT OF THEDISCLOSURE Preparation of u,/3'-unsaturated carbocyclic ketones byreacting a methylene phosphonium ylid or a mono-substituted methylenephosphonium ylid with an enol lactone.

This application is a continuation-in-part of application Ser. No.686,477 filed Dec. 4, 1967, and now US. Pat. No. 3,524,886 andapplication Ser. No. 747,466 filed July 25, 1968.

The present invention relates to the production of unsaturatedcarbocyclic ketones.

More particularly, this invention relates to a novel process which hasgeneral utility for the conversion of enol lactones into nae-unsaturatedcarbocyclic ketones.

The expression enol lactone, as used herein, refers to an unsaturatedlactone having a,/8-ethylenic unsaturation in respect to -theheterocyclic oxygen atom. The expression m,B-unsaturated carbocyclicketone, as used herein, refers to a carbocyclic ketone havinga,[3-ethylenic unsaturation in respect to the keto group.

Prior to the present invention, enol lactones were converted intou,B-unsaturated carbocyclic ketones by a twostep process which involvedreacting the enol lactone with about one equivalent of a Grignardreagent, for example, methylmagnesium chloride, to open the lactone ringand thereafter the thus-obtained diketonic intermediate product wascyclized by treatment with acid or alkali to obtain the carbocyclicketone. See, for example, US. Pats. 3,057,907 and 3,321,489 and FrenchPat. 1,359,675. In addition to the disadvantage that the conversion ofenol lactones into carbocyclic ketones requires at least two steps,prior methods are often difficult to control, unsuitable for 5-memberedring systems, and of very narrow utility in that the a,,8-unsaturatedcarbocyclic ketones ob tainable are very limited.

A primary object of the present invention, therefore, is to provide aprocess for the production of a,B-unsaturated carbocyclic ketones fromenol lactons which overcomes the aforementioned disadvantages. Anotherobject of the present invention is to provide a process for theproduction of a,;8-unsaturated carbocyclic ketones which is economicaland simple to operate but yet of great flexibility or adaptability inrespect to the type of a,/8-unsaturated carbocyclic ketone that can beproduced. Another object of this invention is to provide a single-stepprocess for the production of a,{i-unsaturated carbocyclic ketones.Still another object of the present invention is to provide a processfor the production of u,,8unsaturated carbocyclic ketones which isuseful in the total synthesis of steroids and to novel intermediatestherefor. Other objects, advantages and meritorious features of thepresent invention ice will become apparent as the invention is describedin more detail hereinafter.

In accordance with the foregoing objects of the present invention, therehas been discovered a very versatile process for the production ofa,}8unsaturated carbocyclic ketones which comprises reacting, undersubstantially anhydrous conditions in an organic solvent inert to thereaction, an enol lactone with a phosphonium ylid selected from thegroup consisting of methylenephosphonium ylids and mono-substitutedmethylenephosphonium ylids.

The process of the present invention is applicable to the conversion ofenol lactones into o e-unsaturated carbocyclic ketones in general. Theenol lactone can be either a monocyclic enol lactone or a polycycliccompound such as bicyclic, tricyclic, and tetracyclic enol latonesdepending upon the c p-unsaturated carbocyclic ketone desired to beobtained. The process of the present invention is particularly suitablefor enol lactone starting materials wherein the heterocyclic ringthereof contains at least 5 members and mono-ethylenic unsaturation. Theenol lactones which can be converted into 0:,{3-11I1S8tl113t8dcarbocyclic ketones by the process of this invention are too numerous tolist. Exemplary of the monocyclic and polycyclic enol lactones which canbe used in the process of the present invention area,a,y-trimethylbut-Z-enolide,

A -valeryl lactone,

isocoumarin,

3-methyl-6,8-dimethoxyisocourmarin,

3-phenylisocoumarin,

3-benzoyl-7 ,S-dimethoxyisocournarin,

3-chloroisococumarin,

benzal phthalide,

5,6,7-trimethoxyisocoumarin,

fi-lactone of 1 fi-hYdIOXY-ZB-HlCthYl-Zoc- (2'-carboxyethyl) -3-hydroxycyc1opent-3 -ene,

fi-lactone of 1 /3-hydroxy-4- (2'-carboxyethyl) 5 -hydroxy- 7a,B-methyl3act,4;3,7,7a-tetrahydroindane,

4-oxa-17,6-acetoxyandrost-5-en-3-one,

3-ethoxy-17-oxa-D-homoestra-1,3,5 10),15-tetraen- 17-one,

4-oxacholest-5-en-3-one,

17,20;20,2l-bis-methylenedioxy-4-oxa-1lfi-hydroxypregn-5-en-3-one, and

3-methoxy-l6-oxaestra-1,3,5 10) ,8,l4-pentaen-l7-one.

The phosphonium ylids which are useful in the production ofcap-unsaturated carbocyclic ketones in accordance with the process ofthe present invention are the methylene phosphonium ylids and themono-substituted methylene phosphonium ylids. Methylene phosphoniumylids and mono-substituted methylene phosphonium ylids useful in thepresent invention are illustrated by the following Formulas A and B,respectively:

R\ R R P on 1 R7 2 1 P can wherein each R is independently selected fromthe groups consisting of substituted and unsubstituted, saturated andunsaturated, aliphatic, carbocyclic and carbocyclic-aliphatic radicalsand lower alkoxy radicals and R is selected from the group consisting ofsubstituted and unsubstituted, saturated and unsaturated, aliphatic,carbocyclic and carbocyclic-aliphatic radicals.

wherein, R and R are as defined above.

Phosphonium ylids of Formulas A and B above can be prepared, forexample, by the reaction of a tri-substit uted phosphonium halide, e.g.the bromide or chloride, with a reagent, e.g. a base, capable ofremoving hydrogen halide. Tri-substituted phosphonium halides can beprepared by known methods, such as by reacting a tertiary phosphine withan organic halide or a halogen acid. Suitable reagents which can removehydrogen halide are organo metallic compounds, such as alkyl and aryllithium, alkyl and aryl magnesium halides, alkali metal acetylides,alkali metal amides or alkali metal or alkaline earth alcoholates. Theformation of the ylid can be carried out in inert solvents such asether, tetrahydrofuran or dioxane and preferably in an oxygen-freeatmosphere. The method for preparing the phosphonium ylid is not part ofthe present invention. Suitable procedures for the formation of andexamples of methylene phosphonium ylids and mono-substituted methylenephosphonium ylids useful in the present invention are described by A. W.Johnson, Ylid Chemistry, Academic Press, Inc., New York (1966) S.Trippett, Quarterly Reviews 16, pp. 406-440 (1962); S. Trippett,Advances in Organic Chemistry, vol. I, Inter-Science, New York, pp.83-102 (1960); and A. Maercker, Organic Reactions, vol. 14, John Wiley &Sons, New York, pp. 270-490 (1965) and in US. Pats. 2,905,717;2,917,523; 2,917,524; 2,950,321; 2,957,933; 3,078,256; 3,130,219;3,152,152; and 3,347,932.

Methylene phosphonium ylids and mono-substituted methylene phosphoniumylids are sometimes unstable compounds which react easily with oxygenand on standing for any appreciable period of time. Thus, in thepractice of the process of the present invention, it is preferable touse a tricarbocyclic phosphonium ylid such as saturated tricarbocyclics,e.g. tricyclohexyl, and unsaturated tricarbocyclics (i.e. tri-monoaryls)such as triphenyl, tritolyl, trianisyl, trichlorophenyl, and the like,or tri(carbocyclic-aliphatic) phosphonium ylids such as trrbenzyl, andthe like, and not to isolate the phosphonium ylid but rather to react itwith the enol lactone in situ.

While the methylene phosphonium ylids and mono-sub stituted methylenephosphonium ylids which can be employed in the process of the presentinvention are too numerous to list here, they can be exemplified by thefollowing:

decompose methylenetrimethylphosphorane,methylenetricyclohexylphosphorane, methylenetriphenylphosphorane,methylenetti-N-piperidylphosphorane, methylenetri-N-morpholinophosphorane, methylenetrip-tolyl phosphorane, methylenetri-(p-anisyl pho sphorane, methylenetri-(n butyl)phosphorane,methylenediallylmethylphosphorane, methylenediphenylethylphosphorane,methylenedimethylphenylphosphorane, methylenedimethylp-methoxyphenylphosphorane, methylenediallylphenylphosphorane,methylenetribenzylphosphorane, rnethylenediphenyltolylphosphorane,methylmethylenetriphenylphosphorane, (ethylidenetriphenylphosphorane)3-cycloethylenedioxybutylmethylenetriphenylphosphorane,3,3-dimethoxypropylmethylenetriphenylphosphorane,ethylmethylenetriphenylphosphorane,n-propylmethylenetriphenylphosphorane, and the like.

In practicing the conversion of an enol lactone into the corresponding ad-unsaturated carbocyclic ketone 1n accordance with the process of thepresent invention, the reaction is carried out using about equal molaramounts of the phosphonium ylid and enol lactone. M0re than one molarequivalent of the phosphonium ylid can be used but it is generallydisadvantageous to do so because in some cases the excess reagent mayreact further with the carbonyl group of the desired carbocyclic ketone.Thus, it is preferred to use about one molar equlvalent of thephosphonium ylid or a modest excess such as up to about 1.2 molarequivalents. Any organic solvent can be used for the reaction medium solong as it is inert to the reaction and reagents. Suitable organicsolvents are set forth in the references listed hereinabove and includehydrocarbons such as benzene, toluene, and the like; ethers such astetrahydrofuran, dioxane, monoglyme, diglyme, and the like;dialkylsulfoxides such as dimethylsulfoxide, and the like; and mixturesthereof. When the phosphonium ylid is prepared in situ, the enol lactonecan be introduced as a solution using the same solvent as that used forthe preparation of the ylid. The reaction generally goes to completionin from about 0.5 hours to about 48 hours depending upon such factors astemperature and the relative reactivity of the ylid and enol lactone.The reaction temperature can vary from about -40 C. to the refluxtemperature of the reaction mixture depending upon such factors as thestability of the ylid, the relative reactivity of the ylid and enollactone being reacted and the time in which it is desired to completethe reaction. In the case of the more stable ylids derived from, forexample, triarylphosphonium halides, such asmethylenetriphenylphosphorane, it is best to employ reactiontemperatures of about room temperature to elevated temperatures, such asthe reflux temperature of the reaction mixture, in order to complete thereaction within a shorter period of time.

There is formed an intermediate ylid which in some cases can beisolated, if desired, or the reaction continued without interruption toform the a o-unsaturated carbocyclic ketone. As shown more fullyhereinafter, whether an intermediate ylid is stormed that can beisolated is dependent upon the reactivity of the particular phosphoniumylid and enol lactone being reacted, the solvent medium and the reactiontemperature. If it is desired to isolate the intermediate phosphoniumylid, the enol lactone and phosphonium ylid A or B are preferably mixedtogether at room temperature or below, preferably about 0 C. to 15 C. Ifit is desired to not to isolate the intermediate ylid, the reaction canbe continued without interruption or it can be continued moreefiiciently by the addition of a lower monohydn'c aliphatic alcohol,such as methanol, ethanol, isopropanol, t-butanol, and the. like, withor without the addition of a base such as an alkali metal alkoxide orbydroxide, such as sodium methoxide, sodium ethoxide, sodium hydroxide,potassium hydroxide, potassium methoxide, sodium t-butoxide, and thelike. The lower alcohol or an alcohol containing a base should be addedafter the enol lactone and phosphonium ylid have been comrningled orpreferably after the disappearance of the initial phosphonium ylid whichcan be followed by thin layer chromatography. A part or all of theoriginal solvent can first be removed, if desired, and the alcohol, withor without base, added thereafter. The amount of lower alcohol addedshould generally be such as to provide at least about 10% by volume ofthe total amount of solvent in the reaction mixture, preferably fromabout 25% to The amount of base included in the alcohol is not critical,a small amount generally being sufiicient. The most advantageous amountof base is easily determinable by routine experimentation givingconsideration to the enol lactone, phosphonium ylid and solvent beingemployed. In the case of solvents such as diglyme, monoglyme,dialkylsulfoxide, and the like, if it is not desired to isolate the ylidintermediate, it has been found to be advantageous to include or addafter commingling of the enol lactone and ylid from about to 75%,preferably 25% to 50%, by volume of the total solvent of a dipolaraprotic solvent, such as hexamethylphosphoramide, dimethylformamide,dimethylacetamide, and the like. A particularly preferred reactionsolvent is diglyme in that the process is very efiicient in terms oftime and yield. In the foregoing methods, when it is not desired toisolate the ylid, the efficiency of the reaction is generally increasedby increasing the reaction temperature to above room temperature, suchas reflux temperature.

For optimum results, it is important that the reaction be conductedunder as near anhydrous conditions as possible and preferably under aninert oxygen-free atmosphere such as nitrogen, argon, and the like.While the concentration of the enol lactone and ylid does not appear tobe critical, it is preferred to operate at low concentrations of theorder of about two to about twenty-five percent by weight of thereaction medium. The foregoing reaction conditions are largely dependentupon the particular phosphonium ylid and enol lactone employed and arepresented as a guide. Provided with the foregoing and the exampleshereinafter, the most advantageous or optimum conditions and proportionsof the enol lactone and phosphonium ylid for a particularcad-unsaturated carbocyclic ketone are easily determinable by one ofordinary skill in the art using routine experimentation.

In the case of enol lactone starting materials having other carbonylgroups present, e.g. an isolated keto group, it is preferable tointroduce a protecting group prior to the reaction. An isolated ketogroup can be protected as through formation of the corresponding loweralkylene dioxy or ketal, such as ethylenedioxy, propylenedioxy, and thelike, using an alkylene glycol in the presence of acid and the ketogroup regenerated by treatment with acid following formation of the0a,;3-UI1S2tlllfit6d carbocyclic ketone. Alternatively, an isolated ketogroup can be reduced to the free hydroxyl by the use of reducing agents,such as lithium aluminum hydride, lithium tri(t-butoxy) aluminum hydrideor sodium borohydride, and subsequently oxidized using, e.g. chromiumtrioxide or Jones reagent following completion of the reaction. If afree hydroxyl group is present, there may be some reaction of thehydroxy group with the ylid reagent to form the corersponding alkoxideand hence require that an excess of the ylid be used. It is preferred toprotect hydroxyl groups by esterification to a carboxylic ester, such asacetate, benzoate, cyclopentylpropionate, mesitoate, and the like, or byetherification. Since the ester group in somecases will react with theylid to some extent, it is preferred to convert free hydroxyls of thestarting material into an acid labile ether group such astetrahydropyran-Z-yloxy, tetrahydrofuran-Z-yloxy, methoxy, ethoxy,t-butoxy, or methoxymethylenoxy and especially t-butoxy. In general,however, the phosphonium ylid tends to react faster with the enollactone groups.

Depending upon the particular enol lactone starting material, there isformed in some cases Bgy-carbocyclic ketone along with the cp-unsaturated carbocyclic ketone.

The term lower alkyl, as used herein, refers to a saturated aliphatichydrocarbon group, branched or straight chain, containing one to sixcarbon atoms. The term monoaryl refers to phenyl and substituted phenyl,such as tolyl, chlorophenyl, methoxyphenyl, and the like. Carboxylicacyl and carboxylic acyloxy refer to an acyl group and acyloxy group,respectively, containing less than 12 carbon atoms. Typical ester groupsthus include acetate, propionate, butyrate, benzoate, mesitoate,cyclopentylpropionate, enanthate, trimethylacetate, t-butylacetate,adamantoate, and the like.

The novel process of the present invention is particularly useful forthe production of carbocyclic ketones admirably suited for the synthesisof steroids. One application of the process of the present invention isillustrated below in a novel route for the synthesis of l9-nor steroidswherein R is t-butyl and R is lower alkyl.

In the practice of the above process, the novel tricarbocyclic enollactone (I') is reacted with a 3-cycloeth'ylenedioxybutylmethylenesubstituted phosphorane of the following formula:

in which R is as defined above to yield the c p-unsaturatedtricarbocyclic ketone (I1) in which R and R are as defined above. The oe-unsaturated ketone (11) is treated with aqueous organic acid such asacetic acid to yield the dione (1111'). The dione (111) is subjected tocatalytic hydrogenation using, e.g. palladium-on-carbon or bariumsulfate to yield the saturated dione (IV). The saturated dione iscyclized using either acid to afiord 19-nortestosterone (IV) or usingbase to yield the t-butyl ether of l9-nortestosterone (V). Cyclizationwith acid is accomplished with a mineral acid such as sulfuric acid orhydrochloric acid with concomitant removal of the t-butyl group.Suitable bases for cyclization include the alkali hydroxides such assodium hydroxide. The l9-nor steroids of Formulas V and VI are usefulanabolic agents and intermediates for preparing other useful steroidssuch as l7ot-ethynyl-l7/3-hydroxyestr-4-en-3-one (US. 2,744,122) byoxidation followed by ethynylation.

The following examples are provided to illustrate the present invention.Temperature in degrees centigrade.

EXAMPLE 1 (A) To a solution of 5 g. of methylenetriphenylphos horane inml. of dry tetrahydrofuran under nitrogen, there is added one molarequivalent of 3-methoxy-l6- oxaest-ra-l,3,5(10),8,l4-pentaen-l7-one indry tetrahydrofuran. The mixture is allowed to stand at room temperaturefor 18 hours and is then filtered. The filtrate is diluted with waterand then extracted with ether. The ether extracts are combined andconcentrated to furnish a residue which is chromatographed on neutralalumina eluting with benzene to afford 3-methoxy-14B-estra-l,35,(10),8,IS-pentaen l7 one and 3-methoXyeStra-1,3,5 (l0),8,l4- pentaen-l7-onewhich can be further purified by recrystallization from aqueousmethanol.

(B) 0.5 grams of 3-methoxyestra-l,3,5(10)-8,14-pentaen-l7-one in 25 ml.of ethanol is reduced catalytically with 50 mg. of 5%palladium-on-charcoal until a molar equivalent of hydrogen is taken up.The catalyst is filtered off and the filtrate evaporated to dryness toyield 3-methox'y'estra-1,3,5(10),8-tetraen-l7-one which can be convertedinto estrone methyl ether by procedures outlined in Chemistry & Industry(London), 1022 (1960) or into 19-nor-A steroids using the procedure of,for example, U.S. Pat. 3,318,922.

The process of Example 1A is repeated using other tetracyclic enollactones of Formula I as the starting material to yield a s-unsaturatedtetracarbocyclic ketones.

In the above formula, R is hydrogen or lower alkoxy of one to six carbonatoms; R is lower alkyl; R is lower alkyl; R is hydrogen or methyl and Zis a carbon-carbon single bond or double bond between C-6 and -7.

Thus, S-methoxy-l-methy1-16-oxaestra-1,3,5 (10),6,8, l4-hexaen-17-one(I; 'R is hydrogen, each of R R and R is methyl; and Z is a double bond)is used in Example 1A to alford3-methoxy-l5-methyl-l4fi-estra-1,3,5(l0),6-, 8,15-hexaen-17-one.

The tetracyclic enol lactones can be prepared according to the method ofSimpson et al., Tetrahedron Letters, 3209 (1967) or US. Pat. 3,309,383.

By use of the procedure of Example LB, the 0:,5- unsaturatedtetaracarboxylic ketones obtained from the enol lactones (I) can beconverted into aromatic A steroids and 19-nor-A steroids.

EXAMPLE 2 In the above formula, R is lower alkyl and R is 0x0 or loweralkylenedioxy thereof or the group in which R' is hydroxy or carboxylicester thereof or labile ether thereof.

To a solution of 3 g. of methylenetriphenylphosphorane in 60 ml. of drytetrahydrofuran under nitrogen, there is added one molar equivalent ofthe tricyclic enol lactone of Formula II in which R is methyl and R isthe group in which R is benzoyloxy in dry tetrahydrofuran. The mixtureis heated at reflux for about three hours and then allowed to cool toroom temperature. The reaction mixture is filtered and the filtratediluted with Water and then extracted with ether. The ether extracts arecombined and concentrated under reduced pressure. The residue ischromatographed to afford the compound of Formula III in which B2 isbenzoyl (l7B-benzoyloxy-des-A- estr-9-en-5-one) which can be used toprepare therapeutically useful l9-nor or A steroids according to theprocedure of US. Pat. 3,150,152.

(III) To a solution of 6 g. of3-cycloethylenedioxybutylmethylenetriphenylphosphorane in ml. of drytetrahydrofuran under nitrogen, there is added 1.1 molar equivalents ofthe tricyclic enol lactone of Formula II (R is methyl; R is in which Ris benzoyloxy) in tetrahydrofuran. The mixture is heated at reflux forabout two hours and then allowed to cool to about room temperature. Thereaction mixture is concentrated to about 25 ml. and to the concentrateis added 100 ml. of methanol containing 2 g. of KOH. The mixture isheated at reflux for about two hours. The reaction mixture is thenpoured into water and the resulting mixture extracted With ether. Theether extracts are combined, Washed With Water, dried over sodiumsulfate and concentrated under reduced pressure. The residue ischromatographed to afford the ogfi-UnSalurated tricarbocyclic ketone ofFormula V.

The Dip-unsaturated tricarbocyclic ketone of Formula V is usefulintermediate for the preparation of 19-nor steroids using the procedureof, for example, French Pats. 1,369,964 (1964); 1,432,570 (1964);1,452,898 (1965); or Velluz et al., ibid.

The phosphonium ylid employed in this example can be prepared accordingto the procedure of Maercker, ibid, or by the following method.

A solution of 20.9 g. of the ethylene ketal of methyl 3-bromopropylketone (obtained by treating the ketone with ethylene glycol in benzenein the presence of p-toluenesulfonic acid) in 100' ml. of benzene istreated with 20 g. of triphenylphosphine. This mixture is heated atreflux for two hours and then filtered. The solid material thuscollected is washed with benzene, dried in vacuo, and added to 6.5 g. ofbutyl lithium in 50 ml. of dimethylsulfoxide. This mixture is stirreduntil a red solution is obtained indicating completion of the ylidformation. The progress of the reaction can be followed by means of theGilrnan test which is positive so long as unconsumed butyl lithium ispresent.

9 EXAMPLE 4 To a suspension of 4 g. of(4-chloropent-3-enyl)triphenylphosphom'um bromide (VI) in 50 ml. of drydiglyme, there is added 1.1 equivalents of butyl lithium in hexane withstirring under nitrogen. This mixture is stirred for about 25 minutesand then 1.1 equivalents of the tricyclic enol lactone (II; R is methyland R is in which R is benzoyloxy) in 60 ml. of dry diglyme is added.The reaction mixture is allowed to stand at room temperature for abouttwo hours, 30 ml. of hexamethylphoramide is added, and the mixture isthen heated at reflux for about three hours. After cooling, the reactionmixture is diluted with water and then extracted with ether. The etherextracts are combined, washed, dried over magnesium sulfate andevaporated under reduced pressure to afiord the tip-unsaturatedtricarbocyclic ketone (VII; R is benzoyloxy), which can be purifiedfurther by chromatography on alumina.

This procedure is repeated using the tricyclic enol lactone (II) (R ismethyl and R is 31 I....H in which R is t-butoxy) to yield VII (R' ist-butoxy).

The tricarbocyclic ketone (VII) is a useful intermediate for thesynthesis of aromatic A steroids using the procedure of U.S. Pats.3,050,550 and 3,150,152.

The phosphonium bromide (VI) can be prepared according to the followingprocedure.

A mixture of 10 g. of l-bromopentanbone, 100 ml. of carbon tetrachlorideand g. of phosphorus pentachloride is refluxed for hours. The reactionmixture is then cooled, washed with dilute sodium carbonate and water,dried over magnesium sulfate and evaporated to give 1-bromo-4-chloropent-3-ene which is purified by distillation and convertedinto the phosphonium bromide (VI) by treatment with triphenylphosphinein benzene.

EXAMPLE 5 To a suspension of 4 g. of3-(tetrahydropyran-2'-yloxy)-butylmethylenetriphenylphosphorane in 50ml. of monoglyme, there is added 1.1 equivalents of butyl lithium inhexane with stirring under nitrogen. This mixture is stirred for about25 minutes and then 1.1 equivalents of the tricyclic enol lactone (II; Ris methyl and R is R wherein R is t-butoxy) in 60 ml. of dry monoglymeis added. The reaction mixture is allowed to stand at room temperaturefor about three hours and then is concentrated under reduced pressure toabout 40 ml. To the concentrate, there is added 100 ml. of methanolcontaining 2 g. of sodium methoxide. The mixture is heated at reflux forabout four hours. After cooling, the reaction mixture is diluted withwater and then extracted with ether. The ether extracts are combined,washed, dried over magnesium sulfate and evaporated under reducedpressure to afford the tricarbocyclic ketone (VIII) which can beconverted into 19-nor steroids using the procedures referenced inExample 3.

CH3 c(cH (VIII) The compound of Formula VIII is subjected to hydrolysisusing acetic acid followed by oxidation with chromium trioxide inpyridine to afford the compound VIII.

(VIII') A mixture of 10 g. of 1-chloropentan-4-one, ml. of ether and 1g. of lithium aluminum hydride is allowed to stand at 20 C. for 20hours. The reaction mixture is diluted with water and separated. Theorganic phase is washed with water, dried and evaporated to givel-chloropentan-4-ol which is purified by distillation. Two ml. ofdihydropyran is added to a solution of 1 g. of l-chloropentan-4-ol in 15ml. of benzene. About 1 ml. is removed by distillation to removemoisture and 0.4 g. of p-toluenesulfonic acid is added to the cooledsolution. This mixture is allowed to stand at room temperature for fourdays and is then washed with aqueous sodium carbonate solution andwater, dried and evaporated to yield4-(tetrahydropyran-2-yloxy)-1-chloropentane which is treated withtriphenylphosphine in benzene to furnish4-(tetrahydropyran-2'-yloxy)pentyltriphenylphosphonium chloride. Thisphosphonium chloride is then treated with butyl lithium in dry monoglymeto afford the ylid.

EXAMPLE 6 The process of Example 5 is repeated with the exception thatthe ylid employed is an ylid of Formula IX and there is obtained thetricarbocyclic ketone (X) which is useful in the synthesis of2-methyl-19-nor steroids using the procedure of, for example, Velluz etal., ibid.

The phosphonium ylid (IX) can be prepared as follows.

A mixture of 0.5 moles of 1-acetoxypentan-4-one and 0.5 moles ofpiperidine in benzene is refluxed using a water separator until no morewater distills from the reaction mixture. The reaction mixture is thencooled, washed and dried to afford the 1-acetoxypent-3-ene (XI). Amixture of 5 g. of X1 in 100 ml. of dioxane is treated with an excess ofmethyl iodide at 20 C. for 18 hours and then heated at 70 C. for sixhours. The reaction mixture is concentrated to a small volume, dilutedwith water and 1-acetoxy-3-methylpentan-4-one isolated by extractionwith ethyl acetate. A mixture of 0.5 g. of this ketone, 100 mg. ofp-toluenesulfonic acid, 3 ml. of ethylene glycol and 100 ml. of benzeneis refluxed using a water separator for 24 hours. The reaction mixtureis cooled and then 100 ml. of ethanol and 2 g. of potassium 1 1hydroxide are added. This mixture is refluxed for six hours, cooled,diluted with water and the corresponding ethylene ketal is isolated byextraction with ethyl acetate. A solution of 0.1 mole of the ketal in 50ml. of dimethylformamide containing 0.1 mole of triphenylphosphine isreacted with 0.1 mole of carbon tetrabromide at room temperature for 18hours. The mixture is diluted with water and extracted with ether. Theether extracts are combined, dried and evaporated. The residue ischromatographed on 400 g. of alumina eluting with hexanebenzene andbenzene to give the ethylene ketal of 1bromo-3-methylpentan-4-one whichis treated With triphenylphosphine in toluene to aiford4,4ethylenedioxy-3-methylpentyltriphenylphosphonium bromide which upontreatment with butyl lithium in monoglyme furnishes the ylid (IX).

EXAMPLE 7 (XII) cu CH3 4on TL- N y (XIII) in which R is benzoyloxy) inether is added and the reaction mixture allowed to warm to roomtemperature. To the mixture is added 50 ml. of methanol containing 1 g.of aqueous KOI-I and the resulting mixture is heated at reflux for threehours. The reaction mixture is then diluted with water and thenextracted with ether. The ether extracts are combined, washed withwater, dried and evaporated under reduced pressure. The residue ispurified by chromatography on alumina to give the tricarbocyclic ketone(XIII).

The phosphonium bromide (XII) can be obtained according to the followingoutlined procedure.

-01-1 45: CH CH -H (XII) acid isolated by extraction with ethyl acetate.The crude acid (9 g.) is taken up in methanol and treated with 1equivalent of sodium methoxide. The alcohol is evaporated and theresidue dried under reduced pressure. The residue is then suspended indry benzene and treated at 0 C. with an excess of oxalyl chloride. Afterthe evolution of gas ceases, the reaction mixture is allowed to warm toroom temperature and the excess of oxalyl chloride removed byevaporation of the solvent medium to dryness. The resulting acidchloride (2) is taken up in benzene and treated with an excess ofethereal diazomethane. After the formation of the diazoketone iscomplete, the ether is removed and the resulting diazoketone heatedunder reflux in octan-Z-ol until nitrogen evolution ceases. The crudeproduct is purified by distillation and reduced with an excess oflithium aluminum hydride in 200 ml. of tetrahydrofuran under reflux. Thereaction mixture is decomposed by cautious addition of ethyl acetate andthe inorganic salts precipitated by the addition of concentrated sodiumsulfate solution. The solution is then filtered and evaporated to yieldthe alcohol (5) which is purified by distillation. The alcohol (5) isthen treated with phosphorus tribromide in benzene to give the bromide(6) which is converted into the phosphonium salt (XII) by treatment with1 equivalent of triphenylphosphine in benzene.

The tricarbocyclic ketone (XIII) is an excellent intermediate for thepreparation of valuable 19-norandrostene or androstene steroids bymethods disclosed in the Journal of American Chemical Society, 82, #21,5464 (1964).

one 3 (XIV) (xv) To a suspension of 1.5 g. of methyltriphenylphosphoniumbromide in 50 ml. of dry tetrahydrofuran under nitrogen, there is added1.2 equivalents of n-butyl lithium in hexane with stirring. This mixtureis stirred for about 30 minutes and then 1.1 equivalents of the bicyclicenol lactone of Formula XIV in 50 ml. of dry tetrahydrofuran is addedand the resulting mixture heated at reflux for about three hours. Aftercooling to about room temperature, the reaction mixture is diluted withwater and then extracted with ether. The ether extracts are thenconcentrated under reduced pressure to furnish the5,6,7,8-tetrahydro-1fl-benzoyloxy-S-methyI-indane-S-one of Formula XVwhich can be purified by fractional distillation.

The u h-unsaturated bicarbocyclic ketone of Formula XV is a valuableintermediate for the synthesis of steroids using the method of, forexample, Whitehurst et al., US. Pat. 3,317,566.

Using the procedure of this example, bicyclic enol lactones of FormulaXVI can be converted into the corresponding a,fl-t1nsaturatedbicarbocyclic ketone.

e R. R4 u (XVI) In the above formula, R and R are as definedhereinabove.

The procedure of this example is repeated with the ex ception thattetrahydrofuran is replaced by diglyme to which there is added 25% byvolume of hexamethylphosphoramide to give the carboxylic ketone (XV).

The bicyclic enol lactones of Formula XVI can be pre pared according tothe method of French Pat. 1,496,817 (1966) or using the followingmethod.

A mixture of 0.3 g. of Z-methylcyclopentane-l,3-dione, 0.33 ml. ofmethylacrylate and 0.1 g. of potassium t-butoxide in 200 ml. oft-butanol is allowed to stand at about 20 C. for 72 hours. The reactionmixture is washed with water, dilute sodium hydroxide and the water toneutral, dried and evaporated to give 2-methy1-2-(B-carbomethoxyethyl)cyclopentane-1,3-dione which is purified bydistillation.

crr J=o o alcohol which is converted into the corresponding benzoate bytreatment with benzoyl chloride in pyridine. The methyl ester ishydrolyzed to the acid which is then cyclized to furnish the enollactone of Formula XIV.

EXAMPLE 9 OBz cu f CH=P(C H ':H o o C1130 2 2 (XIV) (XVIII) OBz CH3 l(XIX) To 3 g. of the triphenylphosphonium ylid of 'Formula XVIII in 50ml. of dry monoglyme under nitrogen, there is added 1.1 molarequivalents of the enol lactone (XIV) in 75 m1. of dry monoglyme. Thereaction mixture is allowed to stand for seven hours at roomtemperature, 150 ml. of diglyme and 50 ml. of hexamethylphosphoramideare added and then the mixture is heated at reflux for 20 hours. Aftercooling, water is added and the product isolated by extraction withchloroform and purified by chromatography on alumina to afford theindane-S-one of Formula XIX, i.e.5,6,7,8-tetrahydro-1,8-benzoyloxy-4-[(2-mmethoxyphenyl)ethyl]-83-methyl-indan-5-one which is converted into3-methoxyestra-1,3,5(10),8,14-pentaen- 175-01 17-benzoate by treatmentwith p-toluenesulfonic acid in boiling benzene or according to themethod of US. Pat. 3,317,566.

=By repeating the process of this example with the exception that anequivalent amount of the ylid of Formula XX below is used OCH 14 inplace of the ylid of Formula XVIII and there is obtained the novela,fl-unsaturated bicarbocyclic ketone of Formula XXI below.

OB Z CH 3 Other bicyclic enol lactones of Formula XVI can be used in theabove process to yield the corresponding 0:,[3-

The mono-substituted methylene phosphonium ylids (XVII) and (XX)employed in this example can be prepared according to the followingprocedure.

Ten grams of m-methoxycinnamic acid in ml. of ethanol is treated with0.5 g. of pro-hydrogenated 10% palladium-on-charcoal until the uptake ofhydrogen ceases. The catalyst is removed by filtration and the filtrateevaporated to yield 3-(m-methoxyphenyl)-propionic acid.

A solution of 5 g. of the foregoing propionic acid in 100 ml. oftetrahydrofuran is added cautiously to a boiling solution of 250 ml. oftetrahydrofuran containing 3 g. of lithium aluminum hydride. Thereaction mixture is refluxed overnight with stirring and then cooled andthe excess of hydride decomposed by the cautious addition of ethylacetate and then saturated sodium sulfate. The resulting clear solutionis decanted and dried over sodium sulfate. The solvent remaining isremoved by distillation to give 3-(m-methoxyphenyl)propanol which ispurified by distillation in vacuo. One gram of3-(m-methoxyphenyl)propanol in 50 ml. of benzene is boiled with a slightexcess of phosphorous tribromide until thin layer chromatography nolonger indicates the presence of starting alcohol. The reaction mixtureis cooled, Washed with water and dilute sodium carbonate solution, driedover sodium sulfate and concentrated to dryness. The resulting crude3-(m-methoxyphenyl)-propylbrornide is purified by distillation and thenconverted into the phosphonium salt (XVIII') by reaction withtriphenylphosphine in toluene.

By repeating the above procedure using 3,5-dimethoxycinnamic acid inplace of m-methoxycinnamic acid, the corresponding salt (XX) isobtained.

e s 3 2' (CH2) 2 ocH The above salts (XVIII') and (XX) are thenconverted into the phosphonium ylids of Formulas XVIII and XX,respectively, by treatment with a reagent capable of removing hydrogenhalide such as an organo metallic compound, e.g. butyl or phenyl lithiumin an inert organic solvent such as those described hereinabove. Theresulting phosphonium ylid can then be used in situ by adding the enollactone to the ylid in the same or a difierent inert solvent as used inthe formation of the ylid.

Similarly, by using phosphorus trichloride in the above procedure, thechloride salts corresponding to XVIII and XX are obtained. Also, byusing other tri-substituted phosphines in place of triphenylphosphine,e.g., tricyclohexylphosphine, tritolylphosphine, diphenyltolylphosphine,trichlorophenylphosphine, and the like, the correspondingtri-substituted salts and ylids are obtained. By using otherm-loweralkoxycinnamic acids and 3,5-di (lower a1l oxy)cinnamic acids,the corresponding lower alkoxy and di(lower alkoxy) ylids are obtained.

By reacting the enol lactones of Formula XVI with phosphonium ylids ofFormula XXI, the corresponding cup-unsaturated carbocyclic ketones(XXII) are obtained.

2 a a R4 R fLa 3 rr-a R 0 CH (xxx) (XXII) In the above formulas, R R Rand R are as defined hereinabove and R is hydrogen or methyl.

The ylids of Formula )QGI can be prepared according to the followingoutlined procedure wherein R, R and R are as defined above and x ischloro, bromo or iodc M O CO CH R 0 R 0 @m 2 3 A solution of 0.6 molesof the aldehyde (7) and 0.5 moles of methyl a-bromopropionate in 80 ml.of dry benzene is added dropwise to 0.6 moles of zinc dust. After 15 ml.of the solution is added, the mixture is heated to initiate thereaction. The remaining portion of the solution is then added during onehour. The resulting mixture is cooled, washed with water, dried and thenrefluxed with 0.2 g. of p-toluenesulfonic acid for five hours. Aftercooling, the reaction mixture is washed with dilute sodium bicarbonatesolution and water and then dried and purified by distillation to give(8). One gram of (8) in 2.5 ml. of ethanol is hydrogenated with 0.1 g.of palladium/carbon catalyst until 1 molar equivalent of gas is takenup. The catalyst is filtered off and the solvent evaporated to give2-methyl-3-(substituted phenyl)propiom'c acid methyl ester. One gram ofthis ester in 100 ml. of tetrahydrofuran is reduced with 2 g. of lithiumaluminum hydride until thin layer chromatography indicates the absenceof starting ester. The reaction mixture is cooled, treated cautiouslywith an excess of ethyl acetate followed by saturated sodium sulfatesolution. The organic layer is decanted ofl, dried with sodium sulfateand evaporated to give the alcohol (9) which is converted into thecorresponding halide (10) by treatment with phosphorus pent-achloride inbenzene. The halide (10) is converted into the phosphoni-um salt (XXI')by reaction with triphenylphosphine. The salt on 16 treatment withphenyl or butyl lithium affords the ylid (XXI).

Methyl bromo acetate can be used in place of methyl a-bromopropio'nateto obtain the ylid (XXI) in which R is hydrogen.

(xiv) The carbocyclic ketones (XXII) in which R is methyl are usefulintermediates for the synthesis of 7-methyl substituted steroidsfollowing the cyclization procedure of U.S. Pat. 3,317,566.

EXAMPLE 10 To a suspension of 4 g. of 4,4-dimethoxybutylphosphoniumbromide in 50 ml. of dry monoglyme under nitrogen, there is added 1.2equivalents of phenyl lithium in hexane with stirring. This mixture isstirred for about 30 minutes and then 1.1 equivalents of the bicyclicenol lactone (XIV) in 5-0 ml. of dry monoglyme is added. The reactionmixture is heated at reflux for about three hours and then is allowed tocool to room temperature. The reaction mixture is then diluted withwater ,and extracted with ether. The ether extracts are combined,washed, dried over magnesium sulfate and evaporated under reducedpressure. The residue is chromatographed on silica to alford thea,fi-unsaturated bicarbocyclic lretone (XXII).

The above procedure is repeated with the exceptions that monoglyme isreplaced by diglyme containing 40% hexamethylphosphoramide, by volume,and the reaction mixture is refluxed for six hours to yield thebicarbocyclic ketone (XXH).

A mixture of l g. of the bicarbocyclic ketone (XXII), 25 ml. of methanoland 1 ml. of concentrated HCl is boiled 15 minutes. The reaction mixtureis allowed to cool, poured into water and the resulting mixtureseparated. The organic phase is evaporated to dryness to furnish thealdehyde (XXIII) which is taken up in 20 ml. of acetone, cooled to 0 C.and a slight molar excess of Jones reagent (prepared by mixing 26 g. ofchromium trioxide with 23 ml. of concentrated sulfuric acid and dilutingwith water to ml.) is added. Upon completion of the oxidation asfollowed by thin layer chromatography, the reaction mixture is dilutedwith Water and then extracted with ethyl acetate. The ethyl acetateextracts are combined, washed with water, dried and evaporated underreduced pressure to afiord the acid (XXIV) which is a valuableintermediate for the synthesis of known l9-nor-A and -A steroids usefulas therapeutic agents using the procedure of, for example, BelgiumPatent 629,251 (1963); French Patent 1,465,400 (1965); NetherlandsPatent 6414702; or Velluz et al., ibid.

The 4,4-dimethoxybutyltriphenylphosphonium bromide employed in thisexample can be obtained according to the following procedure.

To 0.5 moles of diethylmalonate in 0.5 liters of dry benzene is added0.5 moles of sodium hydride cautiously and the mixture stirred untilhydrogen evolution ceases. Then 0.5 moles ofbromoacetaldehydedimethylacetal [(CH O) CH-CH Br] in 100 ml. of benzeneis added and the mixture stirred overnight followed by refluxing for twohours. The reaction mixture is cooled, washed with water and purified byvacuum distillation to give 5,,8-dirnethoxyethylmalonic acid diethylester. A mixture of g. of this ester in 100 ml. of ethanol containing 5g. of sodium hydroxide is heated under reflux until evolution of carbondioxide ceases. The reaction mixture is then saturated with carbondioxide and evaporated to dryness under vacuum. The residue is suspendedin 50 ml. of dry dimethylformamide to which is added a large excess ofmethyl iodide. The reaction mixture is stirred at room temperature forabout 24 hours and then poured into water. The resulting mixture isextracted with ether and the ether extracts combined, washed with waterand evaporated to give -dimethoxybutyric acid methyl ester which ispurified by distillation. A mixture of 4 g. of this methyl ester, 50 ml.of dry tetrahydrofuran and 1.1 equivalents of lithium aluminum hydrideis refluxed overnight. The reaction mixture is allowed to cool and thendiluted with water. This mixture is extracted with ether and the etherextracts are combined, washed, dried and evaporated to dryness to afford4,4 dimethoxybutanol (OI-I 0 CHCH CH -CH OH] A solution of 0.1 moles of4,4-dimethoxybutanol in 50 ml. of dimethylformamide containing 0.1 molesof triphenylphosphine is allowed to react for 18 hours with 0.1 mole ofcarbon tetrabromide. The mixture is diluted with water and extractedwith ether. The ether extracts are combined, washed with water, driedand evaporated to a crude product which is purified by distillation toyield 4,4-dimethoxybutylbromide. This bromide on treatment withtriphenylphosphine in toluene furnishes4,4-dimethoxybutyltriphenylphosphonium bromide.

By repeating this procedure using carbon tetrachloride in place ofcarbon tetrabromide, there is obtained4,4-dimethoxybutyltriphenylphosphonium chloride.

Also, by using other tri-substituted phosphines in place oftriphenylphosphine in the above procedure, e.g. tri(ptolyl)-phosphine,trichlorophenylphosphine, diphenyltolylphosphine, the correspondingtri-s-ubstituted phosphonium bromide and chloride are obtained.

EXAMPLE 11 A suspension of n-butyltriphenylphosphonium bromide (1.94 g.)in 50 ml. of dry tetrahydrofuran is treated with 1.1 equivalents ofbutyl lithium in hexane under nitrogen. After 15 minutes, 1 g. ofbenzylidenephthalide in ml. of tetrahydrofuran is added and the reactionmixture left overnight. The reaction mixture is then diluted with ethylacetate, washed with water, dried, evaporated and chromatographed onalumina to give 3-benzyl-2-n-propylindenone. This reaction can beoutlined as follows:

1 cu -CH CH 2 2 3 ti 0 @if CH e s Ca -c rt EXAMPLE 12 2.78 g. ofmethyltriphenylphoshponium bromide is suspended in about 25 ml. ofether. Then 320 mg. of butyl lithium is added and the mixturestirred forabout minutes. Then 1 g. of benzylidenephthalide in about 10 ml. oftetrahydrofuran is added and the mixture stirred overnight at roomtemperature. The reaction mixture is diluted with water and thenextracted with ether. The ether extracts are combined, washed withwater, dried and the solvent removed under vacuum. The residue ischromatographed on silica eluting with ethylene chloride: hexane (4:1)to afford 3-benzylidenindan-l-one and a small amount of startingmaterial.

18 EXAMPLE 13 To a suspension of 600 mg. of methyltriphenylphosphoniumbromide in 10 m1. of dry tetrahydrofuran under nitrogen, there is added97 mg. of butyl lithium. Stirring is continued for about 20 minutes andthen 374 mg. of 175-acetoxy-4-oxaandrost-5-en-3-one in 10 ml. of drytetrahydrofuran is added. The reaction mixture is then diluted withwater followed by extraction with ether. The ether extracts arecombined, dried over magnesium sulfate and evaporated to a residue whichis purified by chromatography to yield 17,3-acetoxyandrost-4-en-3-one.

The above procedure is repeated with the exception the reaction mixtureis concentrated to a small volume to which is added 50 ml. of methanolcontaining 1 g. of aqueous KOH and the mixture is then refluxed eighthours to yield 17,8-hydroxyandrost-4-en-3-one.

By using methylmethylenetriphenylphosphorane as the ylid reagent in theprocesses of this example, the corresponding methyl substitutedtetracarbocyclic compound is obtained, i.e.4-methyl-17fi-acetoxyandrost-4-en-3-one.

By using other tetracyclic enol lactones in the above processes in placeof 17/3-acetoxy-4-oxaandrost-5en-3- one as the starting material, e.g.4-oxacholest-5-en-3-one, 3-ethoxy-17-0xa-D-homoestra-1,3,5 (10),15tetraen 17- one, and the like, the corresponding 0:,[3-1111S3t1113t6dtetracarbocyclic ketone is obtained, e.g. cholest-4-en-3-one andB-ethoxy-D-homoestra-1,3,5(10),14-pentaen-17-one.

EXAMPLE 14 To 4 g. of methylenetricyclohexylphosphorane in 50 ml. of drytetrahydrofuran under nitrogen, there is added 1.1 molar equivalents ofa,a,7-trimethylbut-2-enolide in 50 ml. of dry tetrahydrofuran. Thereaction mixture is allowed to stand at about 20 C. for eight hours andthen diluted with water followed by extraction with ether. The etherextracts are combined, washed, dried over magnesium sulfate andevaporated under reduced pressure to afford 3,5,5trimethylcyclohex-2-en-l-one which can be further purified, if desired,by chromatography.

EXAMPLE 15 To a solution of 5 g. of 3cycloethylenedioxybutylmethylenetriphenylphosphorane in 100 ml. of drytetrahydrofuran under nitrogen, there is added 1.1 molar equivalents ofthe enol lactone (I; R is methyl) in tetrahydrofuran. The mixture isheated at reflux for about two hours and then allowed to cool to aboutroom temperature. The reaction mixture is concentrated to about 25 ml.and 100 ml. of methanol containing 2 g. of potassium hydroxide is addedand the mixture refluxed under nitrogen for about 1.5 hours. The mixtureis concentrated under vacuum, diluted with saturated aqueous sodiumchloride and extracted with ether. The ether extracts are combined,washed, dried and evaporated to yield c p-unsaturated tricyclic ketone(11'). The ketone (11') in 50 m1. of aqueous acetic acid is heated on asteam bath (solution temperature about 80) for 1.5 hours. The mixture isconcentrated under vacuum and isolation with ether atfords the dione(III') with the t-butyl group (R) intact. The a,}3 unsaturated dione(III) in 50 ml. of 0.2% triethylamine in aqueous ethanol is hydrogenatedat room temperature and pressure over 5% palladium-on-charcoal until oneequivalent of hydrogen is absorbed (about 15. minutes). The mixture isfiltered and the filtrate evaporated to yield the saturated dione (IV).

A mixture of 20 mg. of the dione (IV), 10 ml. of methanol, 1 ml. ofWater and 0.5 g. of potassium hydroxide is heated under reflux for 2.5hours under nitrogen. The mixture is allowed to cool and then evaporatedunder vacuum. The residue is taken up in ether, washed, dried oversodium sulfate, and evaporated to dryness to yield the t-butyl ether of19-nortestosterone (V'; R is methyl).

A mixture of 15 mg. of the dione (IV), 5 ml. of methanol, 1 ml. of waterand 2 ml. of 37% hydrochloric acid is refluxed under nitrogen for threehours. The solvent is removed under vacuum and isolation with ethergives 19-nortestosterone (VI; R is methyl).

The following procedure can be used for preparing the enol lactones ofFormula I wherein R and R are as defined therein.

OH OR R 4 CO2}! R o\ y (Xxx) (xxxr) URI Y OR: 4 4

c0 11 (1' IXXXII) A suspension of 0.5 g. of the hydroxy acid (XXX; R ismethyl) in 40 ml. of methylene dichloride is cooled to 70 and then 40ml. of isobutylene and 0.6 ml. of 93% sulfuric acid are added. Thisreaction mixture is shaken for 17 hours in a pressure vessel. The vesselis then recooled to --70, opened and the solution poured into aqueoussodium bicarbonate with stirring. Isolation with methylene dichloridegave the ester (XXXI).

A mixture of 0.8 g. of the ester (XXXI; R is methyl), 50 ml. of ethanol,10 ml. of water and g. of potassium hydroxide is heated under reflux for2.5 hours. Solvent is removed, water added, and extraction with ether.The aqueous phase is adjusted to pH 2 and the acid (XXXII) isolated withether.

A mixture of 0.24 g. of the acid (XXXII; R is methyl), 0.6 g. of sodiumacetate and ml. of acetic anhydride is refluxed under nitrogen for fourhours. The reaction mixture is evaporated under vacuum and the residuetreated with ether and aqueous sodium bicarbonate. Isolation with ethergave the tricyclic enol lactone (l; R is methyl).

The hydroxy acids XXX can be prepared using the procedure of Velluz etal., ibid. or French Pat. 1,465,400 (1965) by the reaction of the loweralkyl ester of 5- keto-6-heptenoic acid with a2-loweralkylcyclopentane-l, 3-dione (prepared by the method of US. Pat.3,318,922) in the presence of base, e.g. triethylrnaine followed bycyclization with acid hydrolysis, reduction and hydrogenaalk lo c l Asan alternate method, the hydroxy acid can be prepared by reacting abicyclo enol lactone of Formula XVI (e.g. XVI in which R isethylenedioxy) with 3,3- dimethoxypropylmethylenetriphenylphosphoranefollowed by hydrolysis to the aldehyde, oxidation of the aldehyde to theacid and then hydrogenation with palladium-oncharcoal. The bicyclic enollactones (XVI) can be obtained according to the method of French Pat.1,496,817 (1966) using a 2-loweralkylcyclopentane-1,3-dione and ethylacrylate to yield ethyl5-(1'-loWeralkyl-2,5'-dioxocyclopentyl)propionate. The 2-oxo group isthen moditied, if desired, using conventional procedures such as formingthe corresponding ethylenedioxy or forming the corresponding hydroxyl byreduction and then esterification or etherification and thereafterhydrolysis and cyclization is performed. The tricyclic enol lactones ofFormula II can be similarly prepared using the method of Netherlands6,414,702 (1965).

EXAMPLE 16 In the above formulas, R, 'R and R are as defined hereinaboveand R is hydrogen or one of the following groups:

(A) To a solution of 4 g. of methylenetriphenylphosphorane in ml. of drytetrahydrofuran under nitrogen, there is added 1.1 molar equivalents ofthe bicyclic enol lactone (XVI; R is methyl, R is ethylenedioxy) in ml.of dry tetrahydrofuran at 0 C. The resulting mixture is stirred at 0 C.for about one hour and then is diluted with water followed by extractionwith ether. The ether extracts are washed, dried and evaporated underreduced pressure to yield the intermediate ylid (XXXIII; R is phenyl, Ris methyl, R is ethylenedioxy, R is hydrogen).

(B) A solution of the intermediate ylid obtained in Part A in 100 ml. ofdiglyme and 35 ml. of hexamethylphosphoramide is heated at reflux forabout six hours and then allowed to cool to about room temperaturefollowed by extraction with ether. The ether extracts are washed, driedand evaporated under reduced pressure to yield the bicarbocyclic ketone(XXXIV; R is methyl, R is ethylenedioxy, R is hydrogen) which can befurther purified by chromatography.

By repeating the process of Part A of this example using the phosphoniumylids shown below in place of methylcnetriphenylphosphorane, thecorresponding intermediate phosphonium ylids (XXXIII) are obtained whichare treated according to Part B of this example yielding thecorresponding bicarbocyclic ketones (XXX-1V).

In the above formulas, R is as defined above and alkyl is lower alkyl.

EXAMPLE 17 The process of Part A of Example 16 is repeated using thephosphonium ylids (XXI) in place of methylenetriphenylphosphorane toyield the intermediate ylids (XXXIII) wherein R is the group i CH 3 m 8which are treated according to Part B of Example 16 to yield thecarbocylic ketones (XXII).

EXAMPLE 18 0 (II) ca ({ootvrr) 0R12 or -(cir- ':n-cn

wherein OR is a labile ether group convertible into the correspondinghydroxyl such as tetrahydrofuran-2'- yloxy, tetrahydropyran-2'-yloxy,t-butoxy, methoxy, and the like.

The process of Part A of Example 16 is repeated using the tricyclic enollactone (II; R is methyl, R is ethylenedioxy) in place of the bicyclicenol lactones (XVI) to yield an intermediate ylid (XXXVII; R is methyl,R is ethylenedioxy, R is hydrogen, R is phenyl) which is subjected tothe procedure of Part B of Example 16 to yield a tricarbocyclic ketone(XXXVIII; R is methyl, R is ethylenedioxy, R is hydrogen).

The other intermediate ylids and tricarbocyclic ketones of FormulasXXXVII and XXXVIII, respectively, are also prepared by the foregoingprocedure using the following phosphonium ylids:

EXAMPLE 19 A mixture of 0.5 moles of 1,3-dithiane and 300 ml. oftetrahydrofuran cooled to 30 is treated with 0.5 molar equivalents of1.5 molar n-butyl lithium in hexane under nitrogen and stirred for 15hours at 20. Then 0.5 moles of the tetrahydropyranyl ether of3-bromopropanol in 200 ml. of tetrahydrofuran is added slowly withstirring at -5 and then left for 14 hours at 0 under nitrogen. Theresulting mixture is cooled to -30 and treated with an additional 0.5molar equivalents of 1.5 molar n-butyl lithium in hexane. After 1.5hours, 0.5 moles of 4-chloro-1-bromopent-3-ene in 200 ml. oftetrahydrofuran is added. The reaction mixture is left standing for 18hours at 0 and then allowed to warm to room temperature for four hours.Water is added and the resulting mixture extracted with ether. The etherextracts are combined, washed with water, dried and concentrated. Theresulting dialkylated thiane (XXXIX) is dissolved in methanol andstirred for two hours with 20 ml. of 1% oxalic acid solution. Thereaction mixture is poured into water containing an excess of sodiumcarbonate solution and then extracted with ether to afford thecorresponding free hydroxy compound. A mixture of 2 g. of the freehydroxy compound and 30 ml. of methylene chloride:pyridine (2: 1) iscooled to -70 and then treated with one equivalent of tosyl chloride inmethylene chloride. The mixture is left standing at 0 for 18 hours andthen allowed to warm to room temperature. The mixture is then dilutedwith water and the resulting tosylate isolated by extraction withmethylene chloride and purified by chromatography. The thus-obtainedtosylate is dissolved in dry ethylene glycol containing 0.5 g. ofmercuric chloride. This reaction mixture is allowed to stand overnightand then heated to 60 for five hours. After cooling, water is added andthe corresponding ketal isolated by extraction with ether. The ketal(0.5 g.) in 25 m1. of dry isopropanol and 0.5 g. of lithium bromide isrefluxed for 12 hours. After cooling, the reaction mixture is dilutedwith water and extracted with ether. The resulting bromide (XL) istreated with triphenylphosphine in benzene to afford the phosphoniumbromide (XLI; R is phenyl, x is bromo) which on treatment with butyllithium gives the corresponding ylid.

(XLI) In the above formula, R is as defined above and x is chloro,bromo, or iodo.

By using lithium chloride or lithium iodide in the above process, thephosphonium chloride, or phosphonium iodide are obtained.

B using other tri-substituted phosphines, e.g. tricyclohexyl, tribenzyl,tritolyl, trimethyl, tributyl, and the like, in place oftriphenylphosphine, the corresponding tri-substituted phosphoniumcompounds (XLI) are obtained.

23 EXAMPLE 20 The procedure of Example 19 is repeated with the exceptionthat 4-chloro-l-bromopent-3-ene is replaced with the bromide (6) ofExample 7 and there is obtained the phosphonium halides (XLII) which areconverted into the corresponding ylids by treatment with phenyl lithiumor butyl lithium "CH3 af -ca; (cs -ccs 2 l x (XLII) EXAMPLE 21 Asuspension of 0.5 g. of 1-chloropentan-4-ol in 40 ml. of methylenechloride is cooled to 70 and then 40 ml. of isobutylene and 0.6 ml. of93% sulfuric acid are added. The mixture is shaken for 17 hours in apressure vessel. The vessel is then recooled to 70, opened and thesolution poured into aqueous sodium bicarbonate with stirring. Isolationwith methylene chloride yields the t-butyl ether of 1-chloropentan-4-ol.

A mixture of 0.5 moles of 1,3-dithiane and 300 ml. of tetrahydrofurancooled to 30 is treated with 0.5 molar equivalents of 1.5 molar n-butyllithium in hexane under nitrogen and stirred for 15 hours at 20. Then0.5 moles of the tetrahydropyranyl ether of 3-bromopropanol in 200 ml.of tetrahydrofuran is added slowly with stirring at and then left for 14hours at 0 under nitrogen. The resulting mixture is cooled to 30 andtreated with an additional 0.5 molar equivalents of 1.5 molar n-butyllithium in hexane. After 1.5 hours, 0.5 moles of the t-butyl ether of1-chlor0pentan-4-one in 200 ml. of tetrahydrofuran is added. Thereaction mixture is left standing for 18 hours at 0 and then allowed towarm to room temperature for four hours. Water is added and theresulting mixture extracted with ether. The ether extracts are combined,washed with water, dried and concentrated. The resulting dialkylatedthiane (XLIII) is dissolved in methanol and stirred for 0.5 hour with 20ml. of 1% oxalic acid solution. The reaction mixture is poured intowater containing an excess of sodium carbonate solution and thenextracted with ether to afford the corresponding free hydrox compound. Amixture of 2 g. of the free hydroxy compound and 30 ml. of methylenechloride: pyridine (2: 1) is cooled to 70 and then treated with oneequivalent of tosyl chloride in methylene chloride. The mixture is leftstanding at 0 for 18 hours and then allowed to warm to room temperature.The mixture is then diluted with water and the resulting tosylateisolated by extraction with methylene chloride and purified bychromatography. The tosylate is dissolved in dry ethylene glycolcontaining 0.5 g. of mercuric chloride. The mixture is allowed to standovernight and then heated to 60 for five hours. After cooling, water isadded and the tosylate of the ketal (XLIV) isolated by extraction withether. The ketal (XLIV) is cyclized by treatment in methanol containinghydrogen chloride at 25 for about 12 hours to give thhe tosylate of XLVwhich is converted into the corresponding bromide by treatment withlithium bromide in isopropanol as described above. The bromide istreated with triphenylphosphine in benzene to afford the phosphoniumbromide (XLVI; R is phenyl, x is bromo) which by treatment with butyllithium or phenyl lithium gives the corresponding ylid.

con

(inst) 4.. no k r-cn -en cn \o X OCH In the above formula, R and x areas defined above. The other phosphonium halides of Formula XLVI can beprepared similarly by using lithium chloride, lithium iodide or sodiumiodide in place of lithium bromide and using other tri-substitutedphosphines in place of triphenylphosphine.

EXAMPLE 22 in the above formula, R and x are as defined above.

The 1-halo-4-alkanone compounds can be prepared, for example, byprocedures described in German Pat. No. 801,276 (December, 1950) orlager et al., Arch. Pharm. 293, 896 (1960).

EXAMPLE 23 A mixture of 0.5 moles of 1,3-dithiane and 300 ml. oftetrahydrofuran cooled to 30 is treated with 0.5 molar equivalents of1.5 molar n-butyl lithium in hexane under nitrogen and stirred for 15hours at 20. Then 05 moles of the ethylene ketal of methyl 3-bromopropylketone in 200 ml. of tetrahydrofuran is added slowly with stirring at 5"and then left for 14 hours at 0 under nitrogen. The resulting mixture iscooled to 30 and treated with an additional 0.5 molar equivalents of 1.5molar n-butyl lithium in hexane. After 1.5 hours, 0.5 moles of l-bromo-3-iodopropane in 200 ml. of tetrahydrofuran is added. The resultingmixture is left standing for 18 hours at 0 C. and then allowed to warmto room temperature and stand for four hours. Water is added and theresulting mixture extracted with ether. The ether extracts are combined,washed with water, dried and evaporated to yield the lbromo compound(XLVIII). The l-bromo compound (XLVIII) is dissolved in dry ethyleneglycol containing 0.5 g. of mercuric chloride. The mixture is allowed tostand overnight and then heated to 60 for five hours. After cooling,water is added and the corresponding diketal (XLIX) isolated byextraction with ether. The diketal (XLIX) is treated withtriphenylphosphine in benzene to afford the phosphonium bromide (L; R isphenyl, x is bromo) which on treatment with butyl or phenyl lithiumgives the corresponding ylid. The l-bromo compound (XLVIII) can besimilarly treated with triphenylphosphine to yield the phosphoniumbromide (L;

R is phenyl, x is bromo) which can be converted into the correspondingylid.

In the above formula, R and x are as defined hereinabove. Similarly,other tri-substituted phosphines can be used in place oftriphenylphosphine to prepare other compounds of formulas L and LIwherein R is as defined above.

Example 16 is repeated using an enol lactone (XVI) in which R is methyland R is R1 I....H

wherein R is t-butoxy to afford the corresponding intermediate ylids(XXXIII) and bicarbocyclic compounds (XXXIV) in which R and R are asdefined therein, R is methyl and R is R LE in which R is t-butoxy.

Similarly, Example 17 is repeated using the t-butyl Two grams of theunsaturated bicarbocyclic ketone (LX; R is methyl, R is ethylenedioxy)in 25 ml. of 0.2% triethylamine and 100 m1. of 95% aqueous ethanol ishydrogenated at room temperature and room pressure overpalladium-on-charcoal until one equivalent of hydrogen is absorbed. Themixture is filtered and the filtrate evaporated to yield thecorresponding saturated bicarbocyclic ketone (LXI).

A mixture of one gram of the saturated bicarbocyclic ketone (LXI), 100ml. of methanol, 10 ml. of Water and 20 ml. of 37% hydrochloric acid isheated at reflux for two hours under nitrogen. The solvent is removedunder reduced pressure and isolation with ether affords the unsaturatedtn'carbocyclic diketone (ELXH; R" is oxo) which is hydrogenated usingthe procedure described above to yield the corresponding saturatedtricarbocyclic diketone 26 which is subjected to oxidation usingchromium trioxide in pyridine or Jones reagent to yield saturatedtriketone (LXIII).

Other compounds of Formula LX (prepared as described in Example 16) canbe used in the above procedure to obtain other useful intermediates ofFormula LXHI.

An unsaturated bicarbocyclic ketone (LXIV; R is ethyl, R' isethylenedioxy) is hydrogenated to the corresponding unsaturatedbicarbocyclic ketone which is cyclized using hydrochloric acid accordingto the procedure of the previous example to afford the tricarbocyclicketone (LXV) in which R is ethyl and R is mm. The compound LXV is anintermediate for A -androstenes or retro-steroids using the procedureof, for example, Netherlands 6707-919 (1967).

EXAMPIJE 26 a 7 R4 R7 Til m 5 cu 2 3 2 3 2 cu I cs lmzgccfl/z o (mm)(LXVII) The unsaturated bicarbocyclic ketone (LXVI; R is methyl, R isethylenedioxy) is hydrogenated over palladium-on-charcoal using theprocedure described above to give the corresponding saturatedbicarbocyclic ketone which is cyclized using acid by the proceduresdescribed above to yield the tricarbocyclic ketone (LXVII; R is methyl,R is oxo) which can be converted into 19-nor steroids b methodsdisclosed in Journal of the American Chemical Society 82, #21, 5464(1967).

EXAMPLE 27 The bicarbocyclic ketone (LXVIII; R is ethylenedioxy) issubjected to the procedure of Example 25 to yield the tricarbocyclicketone (LXIX; R is oxo).

Similarly, the bicarbocyclic ketone (LXX; R is ethylenedioxy) can beconverted into the tricarbocyclic ketone (LXIX; R is oxo).

EXAMPLE 2:;

c11 crr I E 0 ca (mu) (mar) Kim-I11 The bicarbocyclic ketone (LXXI; R isethylenedioxy) is treated with acid using the procedure of U.S.3,050,550 to give the triketone (LXXII; R" is 0x0) which is hydrogenatedover palladium-on-charcoal and then cyclized using acid to thetricarbocyclic diketone (LXXIII).

What is claimed is:

1. A process for the production of o e-unsaturated carbocyclic ketonescomprising reacting, under anhydrous conditions in an organic solventinert to the reaction, a phosphonium ylid represented by the formulawherein R is a carbocyclic radical, with an enol lactone represented bythe formula wherein R is methyl or ethyl and R is t-butoxy, said ylidbeing present in at least about equimolar amounts.

2. The process of claim 1 including the step of adding lower monohydricaliphatic alcohol, or lower monohydric aliphatic alcohol and a baseselected from alkali metal hydroxide and alkali metal alkoxidessubsequent to the substantial disappearance of said ylid and thereaction mixture is then maintained at a temperature of from roomtemperature to reflux temperature.

3. The process of claim 1 including the step of adding a dipolar aproticsolvent subsequent to the substantial disappearance of said ylid, andthe reaction mixture is then maintained at a temperature of from roomtemperature to reflux temperature.

4. The process of claim 3 wherein the dipolar solvent ishexamethylphosphoramide and the reaction mixture is maintained at refluxtemperature.

5. The process of claim 1 wherein said organic solvent is diglyme andthe reaction mixture is maintained at reflux temperature.

References Cited Hendrick et a1., J.A.C.S. vol. (1968), pp. 5926-27.

ALEX MAZEL, Primary Examiner I. H. TURNIPSEED, Assistant Examiner US.Cl. X.R.

